TY - JOUR
T1 - Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis
AU - Mosaei, Hamed
AU - Molodtsov, Vadim
AU - Kepplinger, Bernhard
AU - Harbottle, John
AU - Moon, Christopher William
AU - Jeeves, Rose Elizabeth
AU - Ceccaroni, Lucia
AU - Shin, Yeonoh
AU - Morton-Laing, Stephanie
AU - Marrs, Emma Claire Louise
AU - Wills, Corinne
AU - Clegg, William
AU - Yuzenkova, Yulia
AU - Perry, John David
AU - Bacon, Joanna
AU - Errington, Jeff
AU - Allenby, Nicholas Edward Ellis
AU - Hall, Michael John
AU - Murakami, Katsuhiko S.
AU - Zenkin, Nikolay
N1 - Funding Information:
We thank the staff at the MacCHESS for support with crystallographic data collection. We also thank UK Engineering and Physical Sciences Research Council for X-ray crystallography facilities (grant EP/F03637X/1), Dr U. Baisch (Newcastle University) for measuring the CuKalpha diffraction data, Diamond Light Source for access to beamline I19 (award MT8682), Prof. W. McFarlane (Newcastle University) for NMR support, and Dr. J. Gray (Newcastle University) for HRMS analysis. We acknowledge the PHE National Mycobacterium Reference Laboratory (NMRL) for providing M. tuberculosis Beijing strains 1192/015 and 08/00483E. This work was supported by Wellcome Trust Investigator Award 102851 and Leverhulme Trust Prize PLP-2014-229 (to N.Z.), Innovate UK grants 100953 and 131143 (to N.E.E.A.), a Royal Society University Research Fellowship (to Y.Y.), NIH grant GM087350 (to K.S.M.), a Department of Health Grant in Aid and The PHE Pipeline Fund (to J.B.; the views expressed in this publication are those of the authors and not necessarily those of Public Health England or the Department of Health), and UK Medical Research Council studentship MR/N018613/1 (to J.H.).
Funding Information:
We thank the staff at the MacCHESS for support with crystallographic data collection. We also thank UK Engineering and Physical Sciences Research Council for X-ray crystallography facilities (grant EP/F03637X/1 ), Dr U. Baisch (Newcastle University) for measuring the CuKalpha diffraction data, Diamond Light Source for access to beamline I19 (award MT8682), Prof. W. McFarlane (Newcastle University) for NMR support, and Dr. J. Gray (Newcastle University) for HRMS analysis. We acknowledge the PHE National Mycobacterium Reference Laboratory (NMRL) for providing M. tuberculosis Beijing strains 1192/015 and 08/00483E. This work was supported by Wellcome Trust Investigator Award 102851 and Leverhulme Trust Prize PLP-2014-229 (to N.Z.), Innovate UK grants 100953 and 131143 (to N.E.E.A.), a Royal Society University Research Fellowship (to Y.Y.), NIH grant GM087350 (to K.S.M.), a Department of Health Grant in Aid and The PHE Pipeline Fund (to J.B.; the views expressed in this publication are those of the authors and not necessarily those of Public Health England or the Department of Health), and UK Medical Research Council studentship MR/N018613/1 (to J.H.).
Publisher Copyright:
© 2018 The Authors
PY - 2018/10/18
Y1 - 2018/10/18
N2 - Antibiotic-resistant bacterial pathogens pose an urgent healthcare threat, prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A (KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis). The X-ray crystal structures of KglA with the Escherichia coli RNA polymerase holoenzyme and Thermus thermophilus RNA polymerase-promoter complex reveal an altered—compared with rifampicin—conformation of KglA within the rifampicin-binding pocket. Unique deoxysugar and succinate ansa bridge substituents make additional contacts with a separate, hydrophobic pocket of RNA polymerase and preclude the formation of initial dinucleotides, respectively. Previous ansa-chain modifications in the rifamycin series have proven unsuccessful. Thus, KglA represents a key starting point for the development of a new class of ansa-chain derivatized ansamycins to tackle rifampicin resistance. Resistance to rifamycins, inhibitors of bacterial RNA polymerase used for treatment of tuberculosis, is increasing. Mosaei et al. report an analog of the rifamycins, kanglemycin A, that inhibits rifampicin-resistant RNA polymerases and is effective against multidrug-resistant M. tuberculosis, and they describe its mechanism of action.
AB - Antibiotic-resistant bacterial pathogens pose an urgent healthcare threat, prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A (KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis). The X-ray crystal structures of KglA with the Escherichia coli RNA polymerase holoenzyme and Thermus thermophilus RNA polymerase-promoter complex reveal an altered—compared with rifampicin—conformation of KglA within the rifampicin-binding pocket. Unique deoxysugar and succinate ansa bridge substituents make additional contacts with a separate, hydrophobic pocket of RNA polymerase and preclude the formation of initial dinucleotides, respectively. Previous ansa-chain modifications in the rifamycin series have proven unsuccessful. Thus, KglA represents a key starting point for the development of a new class of ansa-chain derivatized ansamycins to tackle rifampicin resistance. Resistance to rifamycins, inhibitors of bacterial RNA polymerase used for treatment of tuberculosis, is increasing. Mosaei et al. report an analog of the rifamycins, kanglemycin A, that inhibits rifampicin-resistant RNA polymerases and is effective against multidrug-resistant M. tuberculosis, and they describe its mechanism of action.
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U2 - 10.1016/j.molcel.2018.08.028
DO - 10.1016/j.molcel.2018.08.028
M3 - Article
C2 - 30244835
AN - SCOPUS:85054466600
SN - 1097-2765
VL - 72
SP - 263-274.e5
JO - Molecular Cell
JF - Molecular Cell
IS - 2
ER -